U.S. patent application number 13/159329 was filed with the patent office on 2011-12-15 for triheptanoin diet for adult polyglucosan body disease (apbd) treatment.
This patent application is currently assigned to Baylor Research Institute. Invention is credited to Fanny Mochel, Raphael Schiffmann.
Application Number | 20110306663 13/159329 |
Document ID | / |
Family ID | 45096717 |
Filed Date | 2011-12-15 |
United States Patent
Application |
20110306663 |
Kind Code |
A1 |
Schiffmann; Raphael ; et
al. |
December 15, 2011 |
TRIHEPTANOIN DIET FOR ADULT POLYGLUCOSAN BODY DISEASE (APBD)
TREATMENT
Abstract
Compositions and methods for the treatment and management of
adult polyglucosan body disease (APBD) are disclosed herein. The
APBD patients studied in the present invention experienced
stabilization of disease progression and limited functional
improvement with dietary triheptanoin (C7TG). The amount of C7TG
administered to the patient daily for 6-8 months was 1-2 g/kg/24
hrs. The present invention demonstrates, for the first time, the
arrest of clinical deterioration with limited functional recovery
in APBD with triheptanoin diet therapy.
Inventors: |
Schiffmann; Raphael;
(Rockwall, TX) ; Mochel; Fanny; (Dallas,
TX) |
Assignee: |
Baylor Research Institute
Dallas
TX
|
Family ID: |
45096717 |
Appl. No.: |
13/159329 |
Filed: |
June 13, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61354472 |
Jun 14, 2010 |
|
|
|
Current U.S.
Class: |
514/547 |
Current CPC
Class: |
A61P 3/02 20180101; A61K
31/215 20130101; A61P 3/00 20180101; A23L 33/10 20160801; A61K
31/23 20130101 |
Class at
Publication: |
514/547 |
International
Class: |
A61K 31/225 20060101
A61K031/225; A61P 3/00 20060101 A61P003/00 |
Claims
1. A method of alleviating symptoms, improving one or more motor
skills, improving a gait, treating adult polyglucosan body disorder
(APBD), or any combinations thereof in a patient, comprising the
steps of: identifying the patient in need of alleviation of
symptoms, improvement of one or more motor skills, improvement of
gait, treatment against the APBD, or any combinations thereof; and
administering to the patient daily a dose of triheptanoin (C7TG),
wherein the C7TG can optionally be mixed in with one or more food
products for oral consumption by the patient.
2. The method of claim 1, wherein the improvement in one or more
motor skills and gait are selected from the group consisting of
increase in unaided walking time, time in cadence, support time,
stride length, step length, and walking speed.
3. The method of claim 1, wherein the patient is on a regular diet,
wherein the regular diet comprises one or more sources of proteins,
carbohydrates, and fats.
4. The method of claim 1, wherein the C7TG comprises 30-35% of a
daily caloric intake of the patient.
5. The method of claim 1, wherein the C7TG comprises 30%, 31%, 32%,
33%, 34%, and 35% of the daily caloric intake of the patient.
6. The method of claim 1, wherein the amount of C7TG administered
to the patient is 1-2 g/kg/24 hrs.
7. The method of claim 1, wherein the amount of C7TG administered
to the patient is 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,
and 2.0 g/kg/24 hrs.
8. The method of claim 1, wherein the dose of C7TG is administered
daily for 6-8 months.
9. The method of claim 1, further comprising the steps of:
monitoring the progression of the therapy by measuring a level of
one or more metabolite markers of APBD in a body fluid of the
patient; comparing the levels of the one or more metabolites with a
baseline level and a control level, wherein the baseline level is
the level of the metabolites in the body fluid of the patient prior
to the commencement of the treatment and the control level is the
level of the metabolites in the body fluid of a healthy subject not
suffering from APBD; and continuing or terminating the therapy,
altering a dose, a frequency, or both of the C7TG based on the
results of the comparison of the metabolite levels.
10. The method of claim 9, wherein the body fluid is selected from
the group consisting of blood, plasma, and urine.
11. The method of claim 1, wherein the C7TG is used to treat one or
more disorders selected from glycogen branching enzyme deficiency
disorders, Andersen disease, Forbes disease, and Danon disease.
12. A composition for alleviating symptoms, improving one or more
motor skills, improving gait, treating adult polyglucosan body
disorder (APBD), or any combinations thereof in a patient
comprising: triheptanoin (C7TG), wherein the C7TG is used as is or
is mixed in with one or more food products for oral administration
for the alleviation of symptoms, improvement of one or more motor
skills, improvement of gait, treatment against APBD, or any
combinations thereof in the patient; and an optional organoleptic
carrier and one or more optional additives selected from the group
consisting of flavoring agents, vitamins, mineral supplements,
protein supplements, coloring agents, and preservatives.
13. The composition of claim 12, wherein the improvement in the one
or more motor skills and gait are selected from the group
consisting of increase in unaided walking time, time in cadence,
support time, stride length, step length, and walking speed.
14. The composition of claim 12, wherein the composition is
administered while maintaining a regular diet in the patient.
15. The composition of claim 12, wherein the C7TG comprises 30-35%
of a daily caloric intake of the patient.
16. The composition of claim 12, wherein the C7TG comprises 30%,
31%, 32%, 33%, 34%, and 35% of the daily caloric intake of the
patient.
17. The composition of claim 12, wherein the amount of C7TG
administered to the patient is 1-2 g/kg/24 hrs.
18. The composition of claim 12, wherein the amount of C7TG
administered to the patient is 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,
1.7, 1.8, 1.9, and 2.0 g/kg/24 hrs.
19. The composition of claim 12, wherein the dose of C7TG is
administered daily for 6-8 months.
20. The composition of claim 12, wherein the composition is used to
treat one or more disorders selected from defective glycogen
branching enzyme deficiency disorders, Andersen disease, Forbes
disease, and Danon disease.
21. A method of alleviating symptoms, improving one or more motor
skills, improving gait, treating adult polyglucosan body disorder
(APBD), or any combinations thereof in a patient comprising the
steps of: identifying the patient in need of alleviation of
symptoms, improvement of one or more motor skills, improvement of
gait, treatment against the APBD, or any combinations thereof; and
administering to the adult patient a physiologically effective
amount of a formulation orally, wherein the formulation comprises
one or more odd-chain triglycerides having the general formula:
##STR00003## wherein, the R.sub.1, R.sub.2, and R.sub.3 are
esterified to the glycerol backbone are each independently fatty
acids comprising odd numbered carbon chains having 5 to 15 carbon
atoms, an optional organoleptic carrier, and one or more optional
additives selected from the group consisting of flavoring agents,
vitamins, mineral supplements, protein supplements, coloring
agents, and preservatives.
22. The method of claim 21, wherein the R.sub.1, R.sub.2, and
R.sub.3 carbon chains are five carbons in length selected from
pentanoin, triheptanoin, pentanoylcarnitine, n-pentadecanoic acid,
five carbon fatty acid precursors, and derivatives thereof.
23. The method of claim 21, wherein at least one of the R.sub.1,
R.sub.2, and R.sub.3 carbon chains are seven carbons in length.
24. The method of claim 21, wherein the odd-chain triglyceride is
triheptanoin.
25. The method of claim 21, wherein the formulation is used to
treat one or more disorders selected from glycogen branching enzyme
deficiency disorders, Andersen disease, Forbes disease, and Danon
disease.
26. A dietary composition for providing a high fat, low
carbohydrate diet to a human subject comprising: one or more medium
chain triglycerides (MCTs) having the general formula: ##STR00004##
wherein, the R.sub.1, R.sub.2, and R.sub.3 are esterified to the
glycerol backbone are each independently fatty acids comprising odd
numbered carbon chains having 5 to 15 carbon atoms; an optional
organoleptic carrier; and one or more optional additives selected
from the group consisting of flavoring agents, vitamins, mineral
supplements, protein supplements, coloring agents, and
preservatives.
27. The composition of claim 26, wherein the R.sub.1, R.sub.2, and
R.sub.3 carbon chains are five carbons in length selected from
pentanoin, triheptanoin, pentanoylcarnitine, n-pentadecanoic acid,
five carbon fatty acid precursors, and derivatives thereof.
28. The composition of claim 26, wherein at least one of R.sub.1,
R.sub.2, and R.sub.3 carbon chains are seven carbons in length.
29. The composition of claim 26, wherein the odd-chain triglyceride
is triheptanoin.
30. The composition of claim 26, wherein the human subject is a
healthy human subject or a human subject suffering from one or more
glycogen brancher enzyme deficiency, adult polyglucosan body
disorder (APBD), Andersen disease, Forbes disease, and Danon
disease.
31. The composition of claim 30, wherein the composition is adapted
for administration to a human subject suspected of having adult
polyglucosan body disorder (APBD).
32. A dietary formulation suitable for human consumption comprising
medium chain triglycerides, odd numbered carbon chain fatty acids
selected from the group consisting of, five seven, and fifteen
carbon fatty acids, and triglycerides thereof or both.
33. The formulation of claim 32, wherein the fatty acid is
pentanoic acid.
34. The formulation of claim 32, wherein the fatty acid is
heptanoic acid.
35. The formulation of claim 32, wherein the odd-chain triglyceride
is triheptanoin.
36. The formulation of claim 32, wherein the composition is used to
treat or alleviate the symptoms associated with one or more
glycogen brancher enzyme deficiency, adult polyglucosan body
disorder (APBD), Andersen disease, Forbes disease, and Danon
disease.
37. The formulation of claim 36, wherein the formulation is adapted
for administration to a patient with APBD.
38. The formulation of claim 32, wherein the formulation is adapted
for oral administration.
39. The formulation of claim 32, wherein the formulation is adapted
for enteral or parenteral administration.
40. A method of treating or alleviating symptoms in an adult
patient suffering from adult polyglucosan body disorder (APBD)
comprising the steps of: identifying the adult patient in need of
treatment or alleviation symptoms against APBD; and administering a
formulation of an odd-chain fatty acid comprising at least one of a
C5, C7, C9, C11, C13, C15, or triglycerides thereof to the patient
in a quantity sufficient to treat or alleviate the symptoms of the
APBD.
41. The method of claim 40, wherein the formulation comprises one
or more optional additives selected from the group consisting of
flavoring agents, vitamins, mineral supplements, protein
supplements, coloring agents, and preservatives.
42. The method of claim 40, wherein the formulation is adapted for
parenteral, enteral, intravenous, or intramuscular administration.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a non-provisional application of
U.S. provisional patent application 61/354,472 filed on Jun. 14,
2010 and entitled "Triheptanoin Diet for Adult Poylglucosan Body
Disease (APBD) Treatment" which is hereby incorporated by reference
in its entirety.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates in general to the field of
treatment agents for metabolic disorders, and more particularly to
the use of diet comprising triheptanoin for the treatment of adult
polyglucosan body disease (APBD).
STATEMENT OF FEDERALLY FUNDED RESEARCH
[0003] None.
REFERENCE TO A SEQUENCE LISTING
[0004] None.
BACKGROUND OF THE INVENTION
[0005] Without limiting the scope of the invention, its background
is described in connection with the use of therapeutic agents for
the detection and treatment of disorders associated with glycogen
brancher enzymes (GBE) including adult polyglucosan body disease
(APBD).
[0006] U.S. Patent Publication No. 20020102737 (Millington et al.
2002) provides methods of screening subjects for lysosomal storage
diseases, preferably glycogen storage diseases, using a
tetrasaccharide as a biomarker. In a more preferred embodiment,
subjects are screened for Pompe disease (i.e., glycogen storage
disease type II). Also provided are neonatal screening assays. The
present invention further provides methods of monitoring the
clinical condition and efficacy of therapeutic treatment in
affected subjects. Further provided are methods of measuring a
tetrasaccharide biomarker by tandem mass spectrometry, preferably,
as part of a neonatal screening assay for Pompe disease.
[0007] U.S. Patent Publication No. 20080085920 (Donello and
Schweighoffer, 2008) describes methods and compositions for the
treatment of conditions including stress-associated, chronic pain,
and neurodegenerative conditions in a mammal using a composition
comprising NB-DNJ or a compound structurally similar thereto. The
neurodegenerative condition is selected from the group consisting
of Motor Neuron Disease (ALS), Parkinsonian Syndromes, multiple
sclerosis, diffuse cerebral cortical atrophy, Lewy-body dementia,
Pick disease, mesolimbocortical dementia, thalamic degeneration,
bulbar palsy, Huntington chorea, cortical-striatal-spinal
degeneration, cortical-basal ganglionic degeneration,
cerebrocerebellar degeneration, familial dementia with spastic
paraparesis, polyglucosan body disease, glaucoma, Shy-Drager
syndrome, olivopontocerebellar atrophy, macular degeneration,
progressive supranuclear palsy, dystonia musculorum deformans,
Hallervorden-Spatz disease, Meige syndrome, familial tremors,
Gilles de la Tourette syndrome, acanthocytic chorea, Friedreich
ataxia, Holmes familial cortical cerebellar atrophy, AIDS related
dementia, Gerstmann-Straussler-Scheinker disease, progressive
spinal muscular atrophy, progressive balbar palsy, primary lateral
sclerosis, hereditary muscular atrophy, spastic paraplegia,
peroneal muscular atrophy, hypertrophic interstitial
polyneuropathy, heredopathia atactica polyneuritiformis, optic
neuropathy, diabetic retinopathy, Alzheimer's disease and
ophthalmoplegia.
SUMMARY OF THE INVENTION
[0008] The present invention describes the use of diet comprising
triheptanoin for alleviation of symptoms, improvement of motor
skills and functions and for the therapy of APBD.
[0009] The present invention is directed towards a method of
alleviating symptoms, improving one or more motor skills, improving
a gait, treating adult polyglucosan body disorder (APBD) or
combinations thereof in a patient, comprising the steps of:
identifying the patient in need of alleviation of symptoms,
improvement of one or more motor skills, improvement of the gait,
treatment against the APBD or combinations thereof and
administering to the patient daily a dose of triheptanoin (C7TG),
wherein the C7TG can optionally be mixed in with one or more food
products for oral consumption by the patient. The improvement in
one or more motor skills and gait are selected from the group
consisting of increase in unaided walking time, time in cadence,
support time, stride length, step length and walking speed.
[0010] In one aspect of the method the patient is on a regular
diet, wherein the regular diet comprises one or more sources of
proteins, carbohydrates, and fats. In another aspect the C7TG
comprises 30-35% of a daily caloric intake of the patient. In
another aspect the C7TG comprises 30%, 31%, 32%, 33%, 34%, and 35%
of the daily caloric intake of the patient. In yet another aspect
the amount of C7TG administered to the patient is 1-2 g/kg/24 hrs,
more specifically the amount of C7TG administered to the patient is
1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 g/kg/24
hrs. As per the method described hereinabove he dose of C7TG is
administered daily for 6-8 months.
[0011] The method of the instant invention further comprising the
steps of: monitoring the progression of the therapy by measuring
the levels of one or more metabolite markers of APBD in a body
fluid of the patient, comparing the levels of the one or more
metabolites with the levels obtained with a baseline level and a
control level, wherein the baseline level is the level of the
metabolites in the body fluid of the patient prior to the
commencement of the treatment and the control level is the level of
the metabolites in the body fluid of a healthy subject not
suffering from APBD, and continuing or terminating the therapy or
altering a dose, a frequency or both of the C7TG based on the
results of the comparison of the metabolite levels. In one aspect
the body fluid is selected from the group consisting of blood,
plasma, and urine. In another aspect the C7TG is used to treat one
or more disorders selected from glycogen branching enzyme
deficiency disorders, Andersen disease, Forbes disease, and Danon
disease.
[0012] In one embodiment the instant invention also discloses a
composition for alleviating symptoms, improving one or more motor
skills, improving a gait, treating adult polyglucosan body disorder
(APBD) or combinations thereof in a patient comprising:
triheptanoin (C7TG), wherein the C7TG is used as is or is mixed in
with one or more food products for oral administration for the
alleviation of symptoms, improvement of one or more motor skills,
improvement of the gait, treatment against the APBD or combinations
thereof in the patient; and, an optional organoleptic carrier and
one or more optional additives selected from the group consisting
of flavoring agents, vitamins, mineral supplements, protein
supplements, coloring agents, and preservatives In one aspect the
improvement in one or more motor skills and gait are selected from
the group consisting of increase in unaided walking time, time in
cadence, support time, stride length, step length, and walking
speed.
[0013] In another aspect the composition is administered while
maintaining a regular diet in the patient. In another aspect the
C7TG comprises 30-35% of a daily caloric intake of the patient,
more specifically the C7TG comprises 30%, 31%, 32%, 33%, 34%, and
35% of the daily caloric intake of the patient. In yet another
aspect the amount of C7TG administered to the patient is 1-2
g/kg/24 hrs. In one aspect the amount of C7TG administered to the
patient is 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0
g/kg/24 hrs, administered daily for 6-8 months. In yet another
aspect the composition is used to treat one or more disorders
selected from glycogen branching enzyme deficiency disorders,
Andersen disease, Forbes disease, and Danon disease.
[0014] In another embodiment the present invention provides a
method of alleviating symptoms, improving one or more motor skills,
improving a gait, treating adult polyglucosan body disorder (APBD)
or combinations thereof in a patient comprising the steps of:
identifying the patient in need of alleviation of symptoms,
improvement of one or more motor skills, improvement of the gait,
treatment against the APBD or combinations thereof and
administering to the adult patient a physiologically effective
amount of a formulation orally, wherein the formulation comprises
one or more odd-chain triglycerides having the general formula:
##STR00001##
[0015] wherein, the R.sub.1, R.sub.2, and R.sub.3 are esterified to
the glycerol backbone are each independently fatty acids comprising
odd numbered carbon chains having 5 to 15 carbon atoms, an optional
organoleptic carrier, and one or more optional additives selected
from the group consisting of flavoring agents, vitamins, mineral
supplements, protein supplements, coloring agents, and
preservatives.
[0016] In one aspect the R.sub.1, R.sub.2, and R.sub.3 carbon
chains are five carbons in length selected from pentanoin,
triheptanoin, pentanoylcarnitine, n-pentadecanoic acid, five carbon
fatty acid precursors, and derivatives thereof. In another aspect
at least one of the R.sub.1, R.sub.2, and R.sub.3 carbon chains are
seven carbons in length. In a specific aspect the odd-chain
triglyceride is triheptanoin. In yet another aspect the formulation
is used to treat one or more disorders selected from glycogen
branching enzyme deficiency disorders, Andersen disease, Forbes
disease, and Danon disease.
[0017] Yet another embodiment of the present invention discloses a
dietary composition for providing a high fat, low carbohydrate diet
to a human subject comprising: one or more medium chain
triglycerides (MCTs) having the general formula:
##STR00002##
[0018] wherein, the R.sub.1, R.sub.2, and R.sub.3 are esterified to
the glycerol backbone are each independently fatty acids comprising
odd numbered carbon chains having 5 to 15 carbon atoms; an optional
organoleptic carrier; and one or more optional additives selected
from the group consisting of flavoring agents, vitamins, mineral
supplements, protein supplements, coloring agents, and
preservatives.
[0019] In one aspect the R.sub.1, R.sub.2, and R.sub.3 carbon
chains are five carbons in length selected from pentanoin,
triheptanoin, pentanoylcarnitine, n-pentadecanoic acid, five carbon
fatty acid precursors, and derivatives thereof. In another aspect
at least one of R.sub.1, R.sub.2, and R.sub.3 carbon chains are
seven carbons in length. In related aspects the odd-chain
triglyceride is triheptanoin and the human subject is a healthy
human subject or a human subject suffering from one or more
glycogen brancher enzyme deficiency, adult polyglucosan body
disorder (APBD), Andersen disease, Forbes disease, and Danon
disease. In yet another aspect the composition is adapted for
administration to a human subject suspected of having adult
polyglucosan body disorder (APBD).
[0020] One embodiment discloses a dietary formulation suitable for
human consumption comprising medium chain triglycerides, odd
numbered carbon chain fatty acids selected from the group
consisting of, five seven, and fifteen carbon fatty acids, and
triglycerides thereof or both. In specific aspects the fatty acid
is pentanoic acid, heptanoic acid and the odd-chain triglyceride is
triheptanoin. In one aspect the composition is used to treat or
alleviate the symptoms associated with one or more glycogen
brancher enzyme deficiency, adult polyglucosan body disorder
(APBD), Andersen disease, Forbes disease, and Danon disease. In a
specific aspect the formulation is adapted for oral administration
to a patient with APBD. In another aspect the formulation is
adapted for enteral or parenteral administration.
[0021] Another embodiment of the present invention describes a
method of treating or alleviating symptoms in an adult patient
suffering from adult polyglucosan body disorder (APBD) comprising
the steps of: identifying the adult patient in need of treatment or
alleviation symptoms against APBD and administering a formulation
of an odd-chain fatty acid comprising at least one of a C5, C7, C9,
C11, C13, C15 or triglyceride thereof, to the patient in a quantity
sufficient to treat or alleviate the symptoms of the APBD. In one
aspect the formulation comprises one or more optional additives
selected from the group consisting of flavoring agents, vitamins,
mineral supplements, protein supplements, coloring agents, and
preservatives. In another aspect the formulation is adapted for
parenteral, enteral, intravenous or intramuscular
administration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] For a more complete understanding of the features and
advantages of the present invention, reference is now made to the
detailed description of the invention along with the accompanying
figures and in which:
[0023] FIG. 1 is a schematic representation showing transport of
C5-ketone bodies across the blood-brain barrier;
[0024] FIG. 2 is a plot showing the results of the 6-minutes walk
tests on the five patients undergoing the Triheptanoin diet therapy
according to an embodiment of the instant invention; and
[0025] FIG. 3 is a plot showing physical Functioning SF-36 scores
of the five ABPD patients on the open-label triheptanoin study.
DETAILED DESCRIPTION OF THE INVENTION
[0026] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts that can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.
[0027] To facilitate the understanding of this invention, a number
of terms are defined below. Terms defined herein have meanings as
commonly understood by a person of ordinary skill in the areas
relevant to the present invention. Terms such as "a", "an" and
"the" are not intended to refer to only a singular entity, but
include the general class of which a specific example may be used
for illustration. The terminology herein is used to describe
specific embodiments of the invention, but their usage does not
delimit the invention, except as outlined in the claims.
[0028] The present invention presents results obtained in an
open-label study with triheptanoin oil in 5 patients with APBD and
GBE1 deficiency showed that within 6 months of treatment, patients
had a significant improvement in the distance walked during 6
minutes (6 minutes walk test). Gait analysis showed stability or
slight improvement over this period of time. No significant adverse
events occurred. SF-36 Health Survey Questionnaire scores tended to
improve in parallel with motor score.
[0029] Adult polyglucosan disease (APBD) is a progressive
neurogenetic disorder characterized by onset in the 4th or 5th
decade of life of neurogenic bladder and progressive difficulty
walking with sensory abnormalities in the lower extremities. The
motor and sensory abnormalities are caused by a myelopathy combined
often with a peripheral neuropathy. After about a decade of disease
progression most patients lose the ability to walk independently
and in the years that follow the weakness progressively involved
the trunk and the upper extremities. The disease often leads to
premature death. Many of the patients with APBD suffer from an
adult form of glycogen storage disease type IV (MIM 232500) cause
by brancher enzyme 1 (GBE1) deficiency. The vast majority of
patients with GBE 1 deficiency are of Ashkenazi Jewish (AJ)
ancestry.
[0030] Overall, the frequency of all glycogen storage diseases is
1:10,000 with GBE1 deficiency constituting about 3% of all glycogen
storage diseases. ABPD with GBE1 deficiency is a very rare disorder
with less than 50 patients described in the English medical
literature. APBD has no known effective treatment that reverses or
even slows the progression of the disease. The mechanism by which
GBE deficiency causes a neurological disorder is not known. One
hypothesis states that the polyglucosan inclusions mechanically
disrupt normal cellular function such as intra-cellular transport.
The present study advances the hypothesis that decreased glycogen
degradation leads to energy deficit in glia and neurons. Therefore,
anaplerotic therapy, i.e. molecules providing intermediates to the
citric acid cycle, may augment cellular energy production thus
preventing or reversing cellular damage.
[0031] As used herein, the terms "subject" or "patient" are
intended to include living organisms that may have one or more one
or more glycogen brancher enzymes (GBE) deficiencies selected from
Andersen disease, Forbes disease, and Danon disease, and adult
polyglucosan body disorder (APBD). Examples of subjects include
humans, monkeys, horses, cows, sheep, goats, dogs, cats, mice,
rats, and transgenic species thereof. Other examples of subjects
include experimental animals such as mice, rats, dogs, cats, goats,
sheep, pigs, and cows. A subject can be a human suffering from, or
suspected of having, against GBE deficiency or APBD.
[0032] As used herein, the phrases "therapeutically effective
dosage" or "therapeutically effective amount" is an amount of a
compound or mixtures of compounds, such as the odd-chain fatty
acids and precursors or derivatives thereof, that reduce the amount
of one or more symptoms of the condition in the infected subject by
at least about 20%, at least about 40%, even more at least about
60%, 80% or even 100% relative to untreated subjects with a
neurological or a neurodegenerative disorder. Active compounds are
administered at a therapeutically effective dosage sufficient to
treat a condition associated with a condition in a subject. For
example, the efficacy of a compound can be evaluated in patients or
animal model systems that may be predictive of efficacy in treating
the disease in humans or animals.
[0033] As used herein the term, "odd-chain fatty acids" is used to
describe fats and oils in foods are made up of basic units called
fatty acids. In the body, these typically travel in three's as
fatty acid chains attached to glycerol, forming a triglyceride. An
odd-chain fatty acid that is attached to glycerol is described
herein as an odd-chain triglyceride. Both the odd-chain fatty acid
and the odd-chain triglyceride are part of the present invention
and are often used interchangeably. For example, when referring to
an odd-chain fatty acid it is possible to substitute with, or
provide as, the odd-chain triglyceride and vice verse.
[0034] Based on their chemical structure, fatty acids are
classified into 3 major categories: monounsaturated,
polyunsaturated, or saturated fats. The oils and fats that people
and animals eat are nearly always mixtures of these 3 types of
fatty acids, with one type predominating. Two specific types of
polyunsaturated fatty acids, linoleic and alpha-linoleic, are
called essential fatty acids. They must be present in the diet in
adequate amounts because they are considered necessary for proper
nutrition and health. Linoleic acid (LA) is an omega-6 fatty acid
and is found in many oils, e.g., corn, safflower, soybean and
sunflower, whole grains and walnuts. Alpha-linoleic acid (ALA) is a
plant precursor of docosahexanoic acid (DHA). Sources of ALA
include seaweeds and green leaves of plants (in very small
amounts), soybeans, walnuts, butternuts, some seeds (flax, chia,
hemp, canola) and the oils extracted from these foods.
[0035] As used herein, the term "nutritionally effective amount" is
used to mean the amount of odd-chain fatty acids and/or odd-chain
triglycerides that will provide a beneficial nutritional effect or
response in a mammal. For example, as with a nutritional response
to vitamin- and mineral-containing dietary supplements varies from
mammal to mammal, it should be understood that nutritionally
effective amounts of the odd-chain fatty acids will vary. Thus,
while one mammal may require a particular profile of vitamins and
minerals present in defined amounts, another mammal may require the
same particular profile of vitamins and minerals present in
different defined amounts.
[0036] When provided as a dietary supplement or additive, the
odd-chain fatty acids and/or odd-chain triglycerides of the
invention has been prepared and administered to mammals in
powdered, reconstitutable powder, liquid-solid suspension, liquid,
capsule, tablet, caplet, lotion and cream dosage forms. The skilled
artisan in the science of formulations can use the odd-chain fatty
acids disclosed herein as a dietary supplement that may be
formulated appropriately for, e.g., irrigation, ophthalmic, otic,
rectal, sublingual, transdermal, buccal, vaginal, or dermal
administration. Thus, other dosage forms such as chewable candy
bar, concentrate, drops, elixir, emulsion, film, gel, granule,
chewing gum, jelly, oil, paste, pastille, pellet, shampoo, rinse,
soap, sponge, suppository, swab, syrup, chewable gelatin form,
chewable tablet and the like, can be used.
[0037] Due to varying diets among people, the dietary odd-chain
fatty acids of the invention may be administered in a wide range of
dosages and formulated in a wide range of dosage unit strengths. It
should be noted that the dosage of the dietary supplement can also
vary according to a particular ailment or disorder that a mammal is
suffering from when taking the supplement. For example, a person
suffering from chronic fatigue syndrome or fibromyalgia will
generally require a dose different than an athlete who is wanting
to attain a nutritional benefit or obtain an increase in mental
focus. An appropriate dose of the dietary supplement can be readily
determined by monitoring patient response, i.e., general health, to
particular doses of the supplement. The appropriate doses of the
supplement and each of the agents can be readily determined in a
like fashion by monitoring patient response, i.e., general health
to particular doses of each.
[0038] The odd-chain fatty acids may be administered simultaneously
or sequentially in one or a combination of dosage forms. While it
is possible and even likely that the present dietary supplement
will provide an immediate overall health benefit, such benefit may
take days, weeks or months to materialize. Nonetheless, the present
dietary odd-chain fatty acid supplement will provide a beneficial
nutritional response in a mammal consuming it.
[0039] The odd-chain fatty acids of the present invention may be
administered, e.g., orally or by subcutaneous, intravenous,
intraperitoneal, etc., administration (e.g. by injection).
Depending on the route of administration, the active compound may
be neutralized, made miscible, at least partially or fully
water-soluble or even coated in a material to protect the odd-chain
fatty acids from the action of bases, acids, enzymes or other
natural conditions that may interfere with their effectiveness,
uptake or metabolic use.
[0040] To administer the therapeutic compound by other than
parenteral administration, it may be necessary to coat the compound
with, or co-administer the compound with, a material to prevent its
inactivation. For example, the therapeutic compound may be
administered to a subject in an appropriate carrier, for example,
emulsifiers, liposomes, or a diluent. Pharmaceutically acceptable
diluents include saline and aqueous buffer solutions. The
therapeutic odd-chain fatty acids may be dispersed in glycerol,
liquid polyethylene glycols, and mixtures thereof and in oils.
Under ordinary conditions of storage and use, these preparations
may contain a preservative to prevent the growth of
microorganisms.
[0041] Pharmaceutical compositions that include the odd-chain fatty
acids of the present invention suitable for injectable use may
include sterile aqueous solutions, dispersions and sterile powders
for the extemporaneous preparation of sterile injectable solutions
or dispersion. In all cases, the composition must be sterile and
must be fluid to the extent that easy syringability exists. It must
be stable under the conditions of manufacture and storage and must
be preserved against the contaminating action of microorganisms
such as bacteria and fungi.
[0042] The odd-chain fatty acids may be provided with a carrier in
a solvent or dispersion medium containing, for example, water,
ethanol, polyol (for example, glycerol, propylene glycol, and
liquid polyethylene glycol, and the like), suitable mixtures
thereof, and vegetable oils. The proper fluidity can be maintained,
for example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and by the use of surfactants. Prevention of the action of
microorganisms can be achieved by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, thimerosal, and the like. In many cases, it will be
preferable to include isotonic agents, for example, sugars, sodium
chloride, or polyalcohols such as mannitol and sorbitol, in the
composition. Prolonged absorption of the injectable compositions
can be brought about by including in the composition an agent,
which delays absorption, for example, aluminum monostearate or
gelatin.
[0043] The odd-chain fatty acids may be provided in one or more
controlled sizes and characteristics with one or more water-soluble
polymers depending on the size and structural requirements of the
patient, e.g., the particles may be small enough to traverse blood
vessels when provided intravenously. Either synthetic or naturally
occurring polymers may be used, and while not limited to this
group, some types of polymers that might be used are
polysaccharides (e.g. dextran, ficoll), proteins (e.g.
poly-lysine), poly(ethylene glycol), or poly(methacrylates).
Different polymers, because of their different size and shape, will
produce different diffusion characteristics for the odd-chain fatty
acids in the target tissue or organ.
[0044] Sterile injectable solutions can be prepared by
incorporating the therapeutic compound in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the
therapeutic compound into a sterile carrier, which contains a basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, methods of preparation
include: vacuum drying, spray freezing, freeze-drying and the like,
which yield a powder of the active ingredient (i.e., the
therapeutic compound) plus any additional desired ingredient from a
previously sterile-filtered solution thereof.
[0045] The odd-chain fatty acids can be orally administered, for
example, with an inert diluent or an assimilable edible carrier.
The therapeutic compound and other ingredients may also be enclosed
in a hard or soft shell gelatin capsule, compressed into tablets,
or incorporated directly into the subject's diet. The odd-chain
fatty acids may be incorporated with one or more excipients for use
in, e.g., ingestible tablets, buccal tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. The amount of
odd-chain fatty acids in the compositions and preparations may, of
course, be varied depending on, e.g., the age, weight, gender,
condition, disease and course of treatment of the individual
patient. Pediatric doses are likely to differ from adult doses as
will be known to the skilled artisan. The amount of the therapeutic
compound in such therapeutically useful compositions is such that a
suitable dosage will be obtained.
[0046] A dosage unit for use with the odd-chain fatty acids
disclosed herein may be a single compound or mixtures thereof with
other compounds, e.g., amino acids, nucleic acids, vitamins,
minerals, pro-vitamins and the like. The compounds may be mixed
together, form ionic or even covalent bonds. For pharmaceutical
purposes the odd-chain fatty acids (e.g., C5, C7, C9, C11, C13
and/or C15) of the present invention may be administered in oral,
intravenous (bolus or infusion), intraperitoneal, subcutaneous, or
intramuscular form, all using dosage forms well known to those of
ordinary skill in the pharmaceutical arts. Depending on the
particular location or method of delivery, different dosage forms,
e.g., tablets, capsules, pills, powders, granules, elixirs,
tinctures, suspensions, syrups, and emulsions may be used to
provide the odd-chain fatty acids of the present invention to a
patient in need of therapy that includes a number of conditions,
e.g., polysaccharide storage diseases, fatigue, low energy, wasting
and the like. The odd-chain fatty acids may also be administered as
any one of known salt forms.
[0047] The total daily amount of odd-chain fatty acids will vary
depending on the condition and needs of a patient. For example, the
odd-chain fatty acids may be provided as a supplemental source of
immediate, short-term, mid-term or long-term energy and may be
provided in formulations that are immediately available, slow
release or extended release. The dosage amount may be measured in
grams per day, as a percentage of kCalories consumed in a day, as a
percentage of the total daily caloric intake, as part of a fixed, a
modified or a diet that changes over time. For example, a patient
may need immediate intervention that "spikes" the amount of
odd-chain fatty acids to approach or reach ketosis. These
"ketogenic" odd-chain fatty acids will then be varied to not have
other side effects, e.g., start with 40% of total caloric intake
per day and then reduced over time as the patient's condition,
symptoms, clinical course and/or metabolic conditions improves. The
range of percentage caloric intake may vary from between about
0.01, 0.1, 1, 2, 5, 10, 15, 20, 22, 25, 30, 35, 40 or even higher
percent, which may include one or more of the odd-chain fatty acids
(e.g., C5, C7, C9, C11, C13 and/or C15 (available from, e.g.,
Sassol, Germany). One way to measure the effect and/or dosing of
the odd-chain fatty acids is to measure the amount that is
detectable in body solids or fluids, e.g., biopsies and blood,
respectively. A wide variety of odd-chain fatty acids metabolites
may be detected from multiple sources, e.g., urine, tears, feces,
blood, sweat, breath and the like.
[0048] For example, when using C7 as the source of odd-chain fatty
acids these can be provided in the form of a triglyceride, e.g.,
tri-heptanoin. The triglyceride triheptanoin is provided in a
concentration sufficient to provide a beneficial effect is most
useful in this aspect of the present invention. The seven-carbon
fatty acid may be provided, e.g.:
TABLE-US-00001 Infants 1-4 g/kg 35% kcalories Children 3-4 g/kg
33-37% kcalories .sup. Adolescent 1-2 g/kg 35% kcalories Adults
0.1-2 g/kg 35% kcalories
[0049] Goals have been set using 4 g/kg (within ideal body weight
(IBW) range) for infants, children, and some adolescents. Goals
have been set using 2 g/kg (within IBW range) for adolescents.
Goals have been set using 2 g/kg (within IBW range) for adults; but
toleration is 1-1.2 g per kg (which is 35% kcal of estimated
needs).
[0050] The odd-chain fatty acids are typically administered in
admixture with suitable pharmaceutical salts, buffers, diluents,
extenders, excipients and/or carriers (collectively referred to
herein as a pharmaceutically acceptable carrier or carrier
materials) selected based on the intended form of administration
and as consistent with conventional pharmaceutical practices.
Depending on the best location for administration, the odd-chain
fatty acids may be formulated to provide, e.g., maximum and/or
consistent dosing for the particular form for oral, rectal,
topical, intravenous injection or parenteral administration. While
the odd-chain fatty acids may be administered alone or pure, they
may also be provided as stable salt form mixed with a
pharmaceutically acceptable carrier. The carrier may be solid or
liquid, depending on the type and/or location of administration
selected.
[0051] Techniques and compositions for making useful dosage forms
using the present invention are described in one or more of the
following references: Ansel, Introduction to Pharmaceutical Dosage
Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th
ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in
Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds.,
1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton,
Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric
Coatings for Pharmaceutical Dosage Forms (Drugs and the
Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);
Pharmaceutical Particulate Carriers: Therapeutic Applications:
Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed.,
1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood
Books in the Biological Sciences. Series in Pharmaceutical
Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.);
Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40
(Gilbert S. Banker, Christopher T. Rhodes, Eds.), and the like,
relevant portions of each incorporated herein by reference.
[0052] Odd-chain fatty acids may be administered in the form of an
emulsion and/or liposome, e.g., small unilamellar vesicles, large
unilamallar vesicles and multilamellar vesicles, whether charged or
uncharged. Liposomes may include one or more: phospholipids (e.g.,
cholesterol), stearylamine and/or phosphatidylcholines, mixtures
thereof, and the like. Examples of emulsifiers for use with the
present invention include: Imwitor 370, Imwitor 375, Imwitor 377,
Imwitor 380 and Imwitor 829.
[0053] The odd-chain fatty acid vesicles may also be coupled to one
or more soluble, biodegradable, bioacceptable polymers as drug
carriers or as a prodrug. Such polymers may include:
polyvinylpyrrolidone, pyran copolymer,
polyhydroxylpropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues, mixtures thereof, and the
like. Furthermore, the vesicles may be coupled one or more
biodegradable polymers to achieve controlled release of the
odd-chain fatty acids. Biodegradable polymers for use with the
present invention include, e.g., polylactic acid, polyglycolic
acid, copolymers of polylactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked
or amphipathic block copolymers of hydrogels, mixtures thereof, and
the like.
[0054] In one embodiment, gelatin capsules (gelcaps) may include
the odd-chain fatty acid in its native state. For oral
administration in a liquid dosage form, the oral drug components
may be combined with any oral, non-toxic, pharmaceutically
acceptable inert carrier such as an emulsifier, a diluent or
solvent (e.g., ethanol), glycerol, water, and the like. Examples of
suitable liquid dosage forms include oily solutions or suspensions
in water, pharmaceutically acceptable fats and oils, alcohols or
other organic solvents, including esters, emulsions, syrups or
elixirs, suspensions, solutions and/or suspensions reconstituted
from non-effervescent granules and even effervescent preparations
reconstituted from effervescent granules. Such liquid dosage forms
may contain, for example, suitable solvents, preservatives,
emulsifying agents, suspending agents, diluents, sweeteners,
thickeners, and melting agents, mixtures thereof, and the like.
[0055] Liquid dosage forms for oral administration may also include
coloring and flavoring agents that increase patient acceptance and
therefore compliance with a dosing regimen. In general, water, a
suitable oil, saline, aqueous dextrose (e.g., glucose, lactose and
related sugar solutions) and glycols (e.g., propylene glycol or
polyethylene glycols) may be used as suitable carriers for
parenteral solutions. Solutions for parenteral administration
include generally, a water-soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffering salts.
Antioxidizing agents such as sodium bisulfite, sodium sulfite
and/or ascorbic acid, either alone or in combination, are suitable
stabilizing agents. Citric acid and its salts and sodium EDTA may
also be included to increase stability. In addition, parenteral
solutions may include pharmaceutically acceptable preservatives,
e.g., benzalkonium chloride, methyl- or propyl-paraben, and/or
chlorobutanol. Suitable pharmaceutical carriers are described in
multiple editions of Remington's Pharmaceutical Sciences, Mack
Publishing Company, a standard reference text in this field,
relevant portions incorporated herein by reference.
[0056] For direct delivery to the nasal passages, sinuses, mouth,
throat, esophagus, trachea, lungs and alveoli, the odd-chain fatty
acids may also be delivered as an intranasal form via use of a
suitable intranasal vehicle. For dermal and transdermal delivery,
the odd-chain fatty acids may be delivered using lotions, creams,
oils, elixirs, serums, transdermal skin patches and the like, as
are well known to those of ordinary skill in that art. Parenteral
and intravenous forms may also include pharmaceutically acceptable
salts and/or minerals and other materials to make them compatible
with the type of injection or delivery system chosen, e.g., a
buffered, isotonic solution.
[0057] To the extent that the odd-chain fatty acids may be made
into a dry powder or form, they may be included in a tablet.
Tablets will generally include, e.g., suitable binders, lubricants,
disintegrating agents, coloring agents, flavoring agents,
flow-inducing agents and/or melting agents. For example, oral
administration may be in a dosage unit form of a tablet, gelcap,
caplet or capsule, the active drug component being combined with a
non-toxic, pharmaceutically acceptable, inert carrier such as
lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,
magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol,
sorbitol, mixtures thereof, and the like. Suitable binders for use
with the present invention include: starch, gelatin, natural sugars
(e.g., glucose or beta-lactose), corn sweeteners, natural and
synthetic gums (e.g., acacia, tragacanth or sodium alginate),
carboxymethylcellulose, polyethylene glycol, waxes, and the like.
Lubricants for use with the invention may include: sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride, mixtures thereof, and the like.
Disintegrators may include: starch, methyl cellulose, agar,
bentonite, xanthan gum, mixtures thereof, and the like.
[0058] Capsules: Capsules may be prepared by filling standard
two-piece hard gelatin capsules each with 10 to 500 milligrams of
powdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50
milligrams of cellulose and 6 milligrams magnesium stearate.
[0059] Soft Gelatin Capsules: The odd-chain fatty acids may be
dissolved in an oil, e.g., a digestible oil such as soybean oil,
cottonseed oil or olive oil. Non-digestible oils may also be used
to have better control over the total caloric intake provided by
the oil. The active ingredient is prepared and injected by using a
positive displacement pump into gelatin to form soft gelatin
capsules containing, e.g., 100-500 milligrams of the active
ingredient. The capsules are washed and dried.
[0060] Tablets: A large number of tablets are prepared by
conventional procedures so that the dosage unit was 100-500
milligrams of active ingredient, 0.2 milligrams of colloidal
silicon dioxide, 5 milligrams of magnesium stearate, 50-275
milligrams of microcrystalline cellulose, 11 milligrams of starch
and 98.8 milligrams of lactose. Appropriate coatings may be applied
to increase palatability or delay absorption.
[0061] To provide an effervescent tablet, appropriate amounts of,
e.g., monosodium citrate and sodium bicarbonate, are blended
together and then roller compacted, in the absence of water, to
form flakes that are then crushed to give granulates. The
granulates are then combined with the active ingredient, drug
and/or salt thereof, conventional beading or filling agents and,
optionally, sweeteners, flavors and lubricants.
[0062] Injectable solution: A parenteral composition suitable for
administration by injection is prepared by stirring sufficient
active ingredient in deionized water and mixed with, e.g., up to
10% by volume propylene glycol, salts and/or water to deliver a
composition, whether in concentrated or ready-to-use form. Given
the nature of the odd-chain fatty acids (alone, partially or
fully-soluble in water) the amount and final concentration of the
odd-chain fatty acids may be varied such that the liquid may be
provided intravenously using syringes and/or standard intravenous
liquids or fluids. The solution will generally be made isotonic
with sodium chloride and sterilized using, e.g.,
ultrafiltration.
[0063] Suspension: An aqueous suspension is prepared for oral
administration so that each 5 ml contain 100 mg of finely divided
active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg
of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025
ml of vanillin.
[0064] Mini-tablets: For mini-tablets, the active ingredient is
compressed into a hardness in the range 6 to 12 Kp. The hardness of
the final tablets is influenced by the linear roller compaction
strength used in preparing the granulates, which are influenced by
the particle size of, e.g., the monosodium hydrogen carbonate and
sodium hydrogen carbonate. For smaller particle sizes, a linear
roller compaction strength of about 15 to 20 KN/cm may be used.
[0065] Kits: The present invention also includes pharmaceutical
kits useful, for example, for providing an immediate source of
alternative cellular energy, e.g., before, during or after surgery.
The dosage will generally be prepared sterile and ready-to-use,
e.g., one or more containers that may be broken (e.g., sealed glass
ampoules), pierced with a syringe for immediate administration or
even a pressurized container. Such kits may further include, if
desired, one or more of various conventional pharmaceutical kit
components, such as, for example, containers with one or more
pharmaceutically acceptable diluents, carriers, additional
containers, etc., as will be readily apparent to those skilled in
the art. Printed instructions, either as inserts or as labels,
indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, may also be included in the kit. It should be
understood that although the specified materials and conditions are
important in practicing the invention, unspecified materials and
conditions are not excluded so long as they do not prevent the
benefits of the invention from being realized.
[0066] Pharmaceutical Dosage Forms: The odd-chain fatty acids of
the present invention may be provided in liquid form or may also be
provided in a capsule, gelcap or other encapsulated form.
Generally, one composition of the present invention is prepared by
adding, e.g., half of the Kaolin clay or other carrier into the
blended followed by addition of a first active salt form, e.g., the
salt form that is less soluble in the final liquid suspension,
e.g., as an emulsion in water. This process is particularly
suitable for very large mixtures, e.g., 500, 1,000, 3,000 or even
5,000 liters.
[0067] One particular method of delivery of the odd-chain fatty
acids of the present invention is in a tablet, capsule or gelcap
that is coated for enteric delivery. Enteric coating relates to a
mixture of pharmaceutically acceptable excipient(s) that is/are
applied to, combined with, mixed with or otherwise added to a
carrier to deliver the medicinal content, in this case one or more
odd-chain fatty acids (e.g., C5, C7, C9, C11, C13 and/or C15,
mixtures and combinations thereof) through the stomach unaltered
for delivery into the intestines. The coating may be applied to a
compressed or molded or extruded tablet, a gelatin capsule, and/or
pellets, beads, granules or particles of the carrier or
composition. The coating may be applied through an aqueous
dispersion or after dissolving in appropriate solvent. Additional
additives and their levels, and selection of a primary coating
material or materials will depend on the following properties:
resistance to dissolution and disintegration in the stomach;
impermeability to gastric fluids and drug/carrier/enzyme while in
the stomach; ability to dissolve or disintegrate rapidly at the
target intestine site; physical and chemical stability during
storage; non-toxicity; easy application as a coating (substrate
friendly); and economical practicality. Methods for enteric coating
are well known in the art.
[0068] Remington's Pharmaceutical Sciences, discloses that enteric
polymer carries generally include carboxyl groups and hydrophobic
groups in the molecule and the enteric polymer is dissolved in a
solvent having a specific pH value through the dissociation of the
carboxyl groups. For instance, commercially available
hydroxypropylmethyl cellulose acetate succinate is a derivative of
hydroxypropylmethyl cellulose, which is substituted with carboxyl
groups (succinoyl groups) and hydrophobic groups (acetyl groups).
Alginic acid, sodium alginate other natural materials may also be
used to provide an enteric coating.
[0069] Other additives and excipients may then be added to the
formulation of the partially water soluble carrier-active odd-chain
fatty acids mixture, e.g., adding Povidone (e.g., Povidone 30),
Xantham gum (or other gums) and Sorbitol to a mixture of Kaolin
Clay to provide a specific example of one formulation of the
present invention. As will be apparent to those of skill in the
art, the actual amount of the partially-excipient soluble active
salt (e.g., non or partially water soluble) may be varied in
accordance with the dissolution characteristics of the active,
which may be further varied by addition of agents that affect the
solubility and/or dissolution of the active in, e.g., water. As
regards a pediatric formulation, the amount of active may be
reduced in accordance with the dosage form approved for pediatric
use.
[0070] One example of a liquid odd-chain fatty acid(s)
pharmaceutical composition may be prepared for enteral or
parenteral use with the following components:
TABLE-US-00002 Components Weight Odd-chain fatty
acid(s)/triglyceride 1.0 Kg emulsifier (e.g., Imwitor 375) 100 gr
Purified water (USP) 2.0 Kg
The formulation may further include, e.g.:
TABLE-US-00003 Glycerin (USP) 500.0 ml Sorbitol Solution, 70% (USP)
500.0 ml Saccharin Sodium (USP) 10.0 gr Citric Acid (USP) 10.0 gr
Sodium Benzoate (NF) 6.0 gr Kollidon 30 330.0 gr Xanthan Gum 200
Mesh 20.0 gr Bubble Gum Flavor 11.1 gr Methylparaben 1.0 gr
Proplyparaben 100 mg Propylene Glycol (USP) 75 ml Additional
ddH.sub.2O QS to 5 liters.
With appropriate increases of the above for scale-up.
[0071] A batch of mixed release odd-chain fatty acids in an
enveloped preparation on a carrier, e.g., beads, may be prepared
with the following components:
TABLE-US-00004 Components Weight Emulsified odd-chain fatty
acids/triglyceride 8.0 mg Carrier 51.7 mg Calcium Stearate 4.0 mg
Talc 4.0 mg Pharmaceutical Glaze 5.5 mg
[0072] When combining odd-chain fatty acids (C5, C7, C9, C11, C13
and/or C15), these may be formulated as follows. A capsule for
extended release of a first active and extended release of a second
active in an enveloped formulation, in a single capsule:
TABLE-US-00005 First Bead Weight Second Bead Weight odd-chain fatty
6.0 mg odd-chain fatty 2.0 mg acid C7 acid C15 Bead 162.9 mg Bead
108.5 mg Lacquer 6 mg Lacquer 3.3 mg Talc 12.6 mg Talc 5 mg Calcium
Stearate 12.6 mg Calcium Stearate 5 mg Capsule 1
[0073] When combining the odd-chain fatty acids, these may be
formulated as follows. A capsule for extended release of a first
active and extended release of a second active in an enveloped
formulation, in a single capsule:
TABLE-US-00006 First Bead Weight Second Bead Weight odd-chain fatty
6.0 mg odd-chain fatty 2.0 mg acid C9 acids C11 Bead 162.9 mg Bead
108.5 mg Lacquer 6 mg Lacquer 3.3 mg Talc 12.6 mg Talc 5 mg Calcium
Stearate 12.6 mg Calcium Stearate 5 mg Mini-capsule 1
[0074] A formulation for extended release of odd-chain fatty acids
of a second active in an enveloped formulation, in a gelcap:
TABLE-US-00007 Component Weight Component Weight odd-chain fatty
6.0 mg odd-chain fatty 2.0 mg acid C13 acid C15 Bead 162.9 mg Bead
108.5 mg Lacquer 6 mg Lacquer 3.3 mg Talc 12.6 mg Talc 5 mg Calcium
Stearate 12.6 mg Calcium Stearate 5 mg Gelcap 1
[0075] A formulation for rectal release of odd-chain fatty acids in
a suppository:
TABLE-US-00008 Component Weight Odd-chain fatty acids 100 mg
Carrier 10 mg Talc 12.6 mg Calcium Stearate 12.6 mg
beeswax/glycerol 1-2 gr
[0076] An enteric-coated soft gelatin capsule that includes the
odd-chain fatty acids (with or without an emulsifier) is made by
coating the odd-chain fatty acids with a lipophilic material to
obtain granules, mixing the granules obtained in step with an oily
matrix, antioxidants and preservatives to form a lipid suspension,
mixing the lipid suspension within a soft gelatin film, and coating
the soft gelatin film to obtain an enteric coated soft gelatin
capsule.
[0077] The odd-chain fatty acid(s), stearic acid and
triethanolamine are heated and mixed to form an emulsified fluid.
The resulting emulsified fluid is mixed well by a homogenizer to
obtain an emulsified suspension and enterically coated. Examples of
formulations include:
TABLE-US-00009 Component Weight Odd-chain Fatty Acids 360.0 g
Stearic acid 78.6 g Ethanolamine 21.4 g Odd-chain Fatty Acids 360.0
g Stearic acid 30.0 g Triethanolamine 20.0 g Odd-chain Fatty Acids
400.0 g Stearic acid 77.0 g Ethanolamine 23.0 g Cetyl alcohol 50.0
g Odd-chain Fatty Acids 245.0 g Stearic acid 38.5 g Ethanolamine
11.5 g Cetyl alcohol 50.0 g Carboxymethyl cellulose 25.0 g
[0078] Adult polyglucosan disease (APBD) is a rare progressive
neurogenetic disorder characterized by onset in the 4th or 5th
decade of life of neurogenic bladder and progressive difficulty
walking with sensory abnormalities in the lower
extremities..sup.1-3 Dementia of the frontal lobe type, cerebellar
abnormalities and seizures may occur in some patients..sup.4,5 The
motor and sensory abnormalities are caused by a myelopathy combined
often with a peripheral neuropathy..sup.6 After about a decade of
disease progression most patient lose the ability to walk
independently and in the years that follow the weakness
progressively involved the trunk and the upper extremities. The
disease often leads to premature death..sup.3,7 No muscle or liver
dysfunction has been reported to date in patients with APBD. Brain
MRI typically shows extensive white matter abnormality in the
cerebrum and brainstem along with atrophy of the spinal
cord..sup.3, 8-12
[0079] The pathological hallmark of this disease is the
accumulation of intracellular polyglucosan bodies in central (both
neurons and glia) and peripheral nervous system cells but also in
muscle and skin tissue..sup.1, 4, 13-16 The neuron perikarya of the
CNS are notably spared. These polyglucosan bodies consist of
amylopectin-like polysaccharide. These findings led to the
discovery that many of these patients suffer from an allelic form
of glycogen storage disease type IV (GSD IV) caused by brancher
enzyme (GBE1) deficiency (MIM 232500)..sup.17-20 Contrary to
children with GSD IV who generally have no residual GBE1 enzyme
activity, patients with APBD and GBE1 deficiency typically have
about 10% residual enzyme activity..sup.18, 21 The vast majority of
patients with GBE1 deficiency are of Ashkenazi Jewish (AJ)
ancestry..sup.3, 19, 20 Interestingly, a number of patients with
reduced brancher enzyme activity and APBD have been found to be
heterozygote for the most common AJ mutation (Lossos et al
unpublished data)..sup.15 These patients usually have residual GBE1
activity similar to those with mutations identified on both alleles
although higher activity has been reported..sup.15 It is not known
whether these are manifesting heterozygotes or whether the
abnormality in the other allele was simply not found.
[0080] Existing therapy: APBD has no known effective treatment that
reverses or even slows the progression of the disease..sup.3
[0081] Mechanism of disease: The mechanism by which GBE1 deficiency
causes a neurological disorder is not known. Based on the
observation that polyglucosan bodies often occupy most of the
diameter of axons, it was hypothesized that these inclusions
mechanically disrupt normal cellular function such as
intra-cellular transport.sup.1, 15 However, no evidence for such a
mechanism has been published.
[0082] Studies described in the instant invention advance the
hypothesis that at least part of the pathology in APBD is the
presence of mostly abnormally branched glycogen causing
dysregulation of glycogen utilization and consequent energy deficit
in nervous system cells. Therefore, anaplerotic therapy comprising
triheptanoin may supply nutrients to the citric acid cycle to
augment cellular energy production thus preventing or reversing
cellular damage in glia and neuronal cells..sup.22, 23
[0083] The hypothesis described hereinabove is based on the fact
that energy deficit as manifested by hypoglycemia or exercise
intolerance is a common mechanism in the glycogen storage diseases
in general including in childhood GSD IV..sup.17 Norwegian forest
cats with GBE1 deficiency (and therefore a model for GSD IV)
develop perinatal/neonatal hypoglycemia that causes stillbirth or
death in the immediate postnatal period..sup.24, 25 Since the
energy requirements of newborn kittens prior to the ability to
nurse depend on degradation of tissue glycogen, the presence of
amylopectin-like glycogen deposits in the muscle tissue of these
GBE1 deficient newborn cats suggests that in the absence of GBE1
tissue glycogen is not efficiently degraded to support energy
metabolism.sup.24 Affected cats may survive the critical immediate
postnatal period with short-term glucose supplementation and show
no obvious clinical signs until 5 months of age..sup.24 Finally, a
patient with adult-onset acid maltase deficiency (Pompe disease)
markedly improved on triheptanoin with a biochemical response
suggesting that this C7 oil spares protein turnover in this
disorder..sup.22
[0084] Preliminary findings in patients with APBD and GBE1
deficiency as described herein indicate that a patient who was able
to performed prolonged submaximal exercise developed symptomatic
hypoglycemia and an open-label study of triheptanoin
supplementation in 5 patients with APBD and GBE1 deficiency showed
evidence of improved motor performance as well as quality of
life.
[0085] Rationale of the use of triheptanoin: Triheptanoin (glyceryl
triheptanoate) is a triglyceride with odd-numbered fatty acids that
is an anaplerotic substance. Anaplerotic therapy is based on the
concept that there may exist an energy deficit in these diseases
that might be improved by providing alternative substrates for the
citric acid cycle (CAC) and therefore enhanced ATP
production..sup.22, 23
[0086] After enteral absorption of triheptanoin, most of the
heptanoate reaching the liver is .beta.-oxidized to
1.times.anaplerotic propionyl-CoA+2.times.acetyl-CoA..sup.23 The
excess acetyl-CoA and propionyl-CoA are channeled to C4- and
C5-ketone bodies, which are exported from the liver to peripheral
tissues..sup.22, 23 The production of these ketone bodies from
dietary triheptanoin occurs even when the meal contains
carbohydrates. This is because the oxidation of heptanoate, a
medium chain fatty acid, in liver mitochondria is not regulated by
the carnitine palmitoyltransferase system, the activity of which is
inhibited by dietary carbohydrates..sup.23 However, triheptanoin
needs to provide at least 30 to 35% of total calories..sup.26
Otherwise, glucose would be the main source of energy supply and
triheptanoin would not need to be oxidized. The C5-ketone bodies
(3-hydroxypentanoate and 3-ketopentanoate) cross the blood brain
barrier and can generate anaplerotic propionyl- and acetyl-CoA for
the brain Krebs cycle..sup.27 The demonstration of the transport of
C5-ketone bodies across the blood-brain barrier was provided by the
treatment of a patient with pyruvate carboxylase deficiency, where
cerebral anaplerosis is primarily impaired.27 The availability of
C5-ketone bodies for cerebral anaplerosis was demonstrated by the
normalization of glutamine and GABA in the CSF of the patient in
the study, as well as the absence of brain pathology..sup.27
Anaplerotic dietary therapy with triheptanoin has been used in
clinical trials to promote energy production in patients with
apparent insufficiency in Krebs cycle function..sup.22, 26-28 The
availability of anaplerotic substrates for the brain and peripheral
nervous system will allow testing the hypothesis that anaplerotic
therapy can slow down or even reverse the ABPD neurodegenerative
process.
[0087] APBD due to GBE deficiency is a very rare progressive
degenerative neurological disorder that has no known effective
treatment. The present study advances the hypothesis that decreased
glycogen degradation leads to energy deficit in glia and neurons.
Therefore, anaplerotic therapy, i.e. compounds providing
intermediates to the citric acid cycle, may augment cellular energy
production thus preventing or reversing cellular damage. The
present inventors hypothesize that treatment with triheptanoin will
stop or reverse the neurological progression of APBD compared to
control oil that has long chain fatty acids. Therefore, the success
of the therapeutic approach described herein would be the first
therapy for a devastating and mostly likely underdiagnosed
disease.
[0088] Use of triheptanoin in animal models: There is currently no
animal model of ABPD with GBE1 deficiency. The principle of
anaplerosis has been shown in isolated rat heart..sup.29 The
mechanical performance of isolated rat heart decreases rapidly when
the perfusate contains only precursors of acetyl-CoA, i.e., acetate
or acetoacetate. Recovery of cardiac mechanical performance follows
the addition of an anaplerotic substrate (pyruvate,
propionylcarnitine) to the perfusate..sup.30, 31 Short-term studies
were conducted in rats to determine the metabolism of
triheptanoin..sup.32
[0089] Use of triheptanoin in humans: After ingestion of
triheptanoin, peripheral tissues receive two precursors of
propionyl-CoA, i.e., heptanoate and C5-ketone bodies. C5-, like
C4-, ketone bodies are natural substrates for the brain and can
target physiological monocarboxylate transporters at the surface
membrane of the blood-brain barrier..sup.33, 34 Brain uptake of
ketone bodies has been demonstrated in humans..sup.35-37 Uptake of
ketone bodies by diffusion or via the monocarboxylate transporters
has been demonstrated in rate neurons and glia..sup.38, 39
[0090] Triheptanoin has been safely and effectively used for the
treatment of long chain fatty acid oxidation defects and patients
with adult-onset carnitine palmitoyltransferase II
deficiency..sup.26, 28 Diet treatment with triheptanoin at 30% to
35% of total daily caloric intake resulted in decreased episodes of
rhabdomyolysis, improvement in pain and cardiac function..sup.26 No
propionyl overload occurred. In our institution, 78 patients have
been receiving chronic triheptanoin supplementation thus far--63
with mitochondrial fat oxidation defects and 14 patients with
glycogen storage diseases including 5 patients with APBD and GBE1
deficiency (unpublished data).
[0091] The demonstration of the transport of C5-ketone bodies
across the blood-brain barrier (FIG. 1) was provided by the
treatment of a patient with pyruvate carboxylase deficiency, where
cerebral anaplerosis is primarily impaired..sup.27 The availability
of C5-ketone bodies for cerebral anaplerosis was also demonstrated
by the normalization of glutamine and GABA in the CSF of this
patient, as well as the absence of brain pathology..sup.27
[0092] Use of triheptanoin in patients with APBD and GBE1
deficiency: In an open-label protocol designed by the present
inventors five patients with APBD and GBE1 deficiency were been
treated for a mean 8.2 months. Ages ranged from 51-66 years and all
were Ashkenazi Jewish. Three patients were able to walk
independently, one walked with the help of a walker and a 5.sup.th
patient was wheelchair bound.
[0093] The patients received triheptanoin oil (Sasol, GmbH Germany)
at a dose of 1-2 g/fg/24 hours in 4 divided doses with food during
3 meals and at bedtime (representing 30-35% of total caloric intake
with a control diet supplemented long chain oil (sunflower oil).
The patients were randomized to either triheptanoin or control oil
for 6 months. Following 6 months, the patients groups will cross
over and the triheptanoin will go to control oil while the initial
control oil group will receive triheptanoin both for another 6
months. The control vegetable oil (Pure Wesson soy oil) was also
administered alone or as part of a meal or a snack to provide about
35% of the caloric intake
[0094] In the event that the plasma levels of propionylcarnitine
increased above 8 .mu.mol/l, the dose of triheptanoin will be
reduced until the decrease of plasma propionylcarnitine is below 8
.mu.mol/l. In the event of an organic acid abnormality such as an
excessive urinary excretion of propionic and/or methylmalonic acid
occur, biotin and/or vitamin B12 respectively were added to the
regimen and normalization of the organic acid and acylcarnitine
profile was verified. Should that not be sufficient the dose was
reduced until normalization occurs. If still abnormal, patient was
be excluded from the study. For GI distress, the dose will first be
taken over a longer period of time (30 minutes), then fiber
oligosaccharides (FOS) was used mixed with triheptanoin oil with a
blender in order to facilitate GI absorption. If GI distress
persisted, triheptanoin dose was reduced by 50% and re-increased
progressively as the problems resolved.
[0095] Baseline evaluation based on the criteria described in Table
I, herein below was performed every 3 months.
[0096] No adverse events (AE) were reported by these patients. The
only AE remotely linked to triheptanoin was the rectal pain
reported by one patient. Two adverse events not related to the
triheptanoin were a broken ankle in one patient and wound treatment
in another. There were no serious AE related to triheptanoin oil.
Safety was also monitored throughout the study by urinary organic
acids and blood acylcarnitine profile analyses. Changes in
metabolic tests related the ingestion of triheptanoin were
identified. Urinary excretion of derivatives of heptanoate
oxidation were detected including pimelate, 3-hydroxypentanoate,
3-ketopentanoate, 3-hydroxypropionate, and methylcitrate--but there
was no evidence of mitochondrial overload from triheptanoin-derived
metabolites. In plasma, there was no substantial increase in either
pentanoylcarnitine (C5) or heptanoylcarnitine (C7) but
propionylcarnitine (C3) increased in most patients. These findings
demonstrate that triheptanoin was catabolized completely without
accumulation of secondary metabolites.
[0097] The outcome measures included: (i) the 6 minutes walk test
and (ii) motion capture gait analysis and (iii) SF-36 Health Survey
Questionnaire. Six minute walk test showed a mean increase of 130
feet (1246.+-.642 to 1376.+-.692; p=0.06). A mean improvement of
10% was observed in the 6-minute walk test over a mean follow up of
8.5 months (n=5, p=0.06). One patient had a 126 feet improvement
(9.5%) at the 25 months time point. Maximal improvement seemed to
occur within the first 6 months of treatment (FIG. 2). Gait
analysis showed improvement over this period of time in cadence,
support time, stride length, step length and walking speed of the 3
patients who were able to walk unaided. SF-36 Health Survey
Questionnaire scores tended to improve in parallel with motor score
(FIG. 3). Physical Function score increased in 4/5 patients on the
SF-36 health survey questionnaire.
TABLE-US-00010 TABLE I Baseline evaluation criteria. Concomitant
medication Informed Consent assessment Vital signs 6-minute walk
test Weight Motion capture gait analysis Height (baseline only)
SF-36 Health Survey Questionnaire Physical and neurological Dietary
Assessment and examination education Serum chemistry laboratory
tests.sup.a Blood acylcarnitine profile.sup.b Quantitative urine
organic acid analysis.sup.c AE assessment .sup.aSerum chemistry
laboratory tests (Comprehensive Metabolic Panel): Na, K, Cl, total
CO.sub.2, total Ca.sup.2+, creatinine, blood urea nitrogen (BUN),
glucose, albumin, total protein, total bilirubin, alkaline
phosphatase, alanine aminotransferase (ALT), and aspartate
aminotransferase (AST). Creatine kinase .sup.bEach patient can
expect a visit of up to 5 days for the initial investigation.
Clinical and laboratory assessment will be carried out with
whatever diet they were receiving on admission. They will then
receive the diet containing triheptanoin or control oil (1-2
grams/Kg/24 hours) for the remainder of the visit with evaluation
of urine organic acids and blood acylcarnitines two days after
triheptanoin (or control oil) initiation which will reflect the
need, if any, for supplemental biotin or cyanocobalamin
[0098] Study Design and Statistical Procedures: This study is a
double blind, cross-over, phase II clinical trial assessing the
effect of triheptanoin on patients with adult polyglucosan body
disease (APBD). Patients will be randomized in a 1:1 ratio to the
two treatment orders (placebo followed by triheptanoin and
triheptanoin followed by placebo) and will remain on each treatment
for 6 months with a 3 days washout period between them.
[0099] Descriptive statistics were given overall and appropriate
classifications (e.g. treatment, time, etc). Continuous variables
were described by their frequency of observations, mean, median,
standard deviation, minimum, and maximum values. Categorical
variables were described by their frequency and percentage.
[0100] The treatment effect on the primary outcome, 6-minute walk
test, will be assessed using linear mixed models to account for
repeated measures. If Y.sub.ijk is the i.sup.th patient using the
j.sup.th treatment (trt) at the k.sup.th time point then the linear
mixed model will be:
Y.sub.ijk=.beta..sub.0+.beta..sub.1*trt.sub.j+.beta..sub.2*time.sub.k+ti-
me.sub.3*trt.sub.j*time.sub.k+b.sub.i+e.sub.ijk (1)
e.sub.ijk.about.Normal (0,.sigma..sup.2) (2)
b.sub.i.about.Normal (0,.sigma..sub.s.sup.2) (3)
[0101] The hypothesis that .beta..sub.1=0 will be used to test for
a triheptanoin effect using an alpha of 0.05. Although no
carry-over effect was anticipated, the time and treatment by time
interaction effects were still assessed to verify this assumption.
If the interaction was found to be significant then the treatment
effect will be assessed by each time point.
[0102] Secondary outcomes were also assessed. For continuous
variables with independent observations comparisons of central
tendency were made using ANOVA or Kruskal-Wallis test. For
dependent observations, linear mixed model analyses were used. For
categorical variables with independent observations
likelihood-ratio chi-square tests were used to univariately test
for differences among groups. For dependent observations McNemar's
or Cochran's Q (for tables larger than 2 by 2) test were used. For
multivariate analyses of binary outcomes generalized linear mixed
models (assuming a binomially distributed outcome and using the
logit link function) were used to account for correlated
observations. A 0.05 level of significance with Bonferroni
correction for multiple comparisons were used. Analyses were
supplemented with appropriate graphics. SAS v9.2 was be used for
the analyses.
[0103] Sample size calculations were based on a cross-over study
design assuming no period or carry-over effects. The detectable
difference in paired means was determined for the obtainable sample
size of 18 patients with a standard deviation, correlation, alpha,
and power of 667.2, 0.90, 0.05, and 0.80 respectively. The standard
deviation and correlation estimates were obtained from the
preliminary results. Based on these values the study is adequate
powered to detect a mean difference of 209 feet between the placebo
and treatment group.
[0104] It is contemplated that any embodiment discussed in this
specification can be implemented with respect to any method, kit,
reagent, or composition of the invention, and vice versa.
Furthermore, compositions of the invention can be used to achieve
methods of the invention.
[0105] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the claims.
[0106] All publications and patent applications mentioned in the
specification are indicative of the level of skill of those skilled
in the art to which this invention pertains. All publications and
patent applications are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
[0107] The use of the word "a" or "an" when used in conjunction
with the term "comprising" in the claims and/or the specification
may mean "one," but it is also consistent with the meaning of "one
or more," "at least one," and "one or more than one." The use of
the term "or" in the claims is used to mean "and/or" unless
explicitly indicated to refer to alternatives only or the
alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or." Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0108] As used in this specification and claim(s), the words
"comprising" (and any form of comprising, such as "comprise" and
"comprises"), "having" (and any form of having, such as "have" and
"has"), "including" (and any form of including, such as "includes"
and "include") or "containing" (and any form of containing, such as
"contains" and "contain") are inclusive or open-ended and do not
exclude additional, unrecited elements or method steps.
[0109] The term "or combinations thereof' as used herein refers to
all permutations and combinations of the listed items preceding the
term. For example, "A, B, C, or combinations thereof' is intended
to include at least one of: A, B, C, AB, AC, BC, or ABC, and if
order is important in a particular context, also BA, CA, CB, CBA,
BCA, ACB, BAC, or CAB. Continuing with this example, expressly
included are combinations that contain repeats of one or more item
or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so
forth. The skilled artisan will understand that typically there is
no limit on the number of items or terms in any combination, unless
otherwise apparent from the context.
[0110] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. All such similar substitutes and modifications apparent
to those skilled in the art are deemed to be within the spirit,
scope and concept of the invention as defined by the appended
claims.
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